Low cobalamin (vitamin B12) levels are frequent, especially in the elderly, several million of whom are affected. Most often the low levels reflect "subclinical cobalamin deficiency", an asymptomatic state marked only by metabolic evidence of cobalamin insufficiency. It is unclear if these persons need intervention because progression to clinical deficiency may be uncommon, and many people with low levels have no deficiency at all. The proposal aims to study whether nitrous oxide (N2O), used in most general anesthesia in the US, worsens cobalamin status in elderly people who have unrecognized subclinical cobalamin deficiency. The reason for concern is that N2O inactivates cobalamin and therefore can cause neurological dysfunction in some patients with underlying clinically expressed cobalamin deficiency. The elderly are known to have an increased risk of postoperative cognitive complications. The study will recruit patients >60 years old who are scheduled for elective surgery in which N2O use for more than 1 hour is planned. Patients will be randomized in a blinded fashion to receive a standard anesthetic regimen of several agents, in which N2O is either included or replaced by air; the two regimens are equally safe and effective. They will undergo cognitive function and depression scale testing, blood testing of cobalamin-related metabolism, and clinical evaluation before surgery and at 48 hours, 14 days and 28 days after surgery. Those with cognitive changes will be treated with cobalamin and reevaluated after 3 months. Statistical analysis will compare the subgroups' metabolic, neuropsychological, demographic, genetic and clinical data. The primary question is what effect routine N2O anesthesia has on metabolic and clinical status related to subclinical cobalamin deficiency. It will also resolve whether or not the combination of N2O and the deficiency can explain the increased rate of postoperative cognitive problems in the elderly, and thus if preoperative or postoperative attention to cobalamin is needed in the elderly. A secondary goal is to extensively study cobalamin-related and homocysteine-related metabolism in these patients and their conditions, particularly as changes evolve after N2O use and later improvement. The clinical study provides a unique opportunity to establish these metabolic details and to compare their interactions with common genetic mutations in the patients that affect enzymes relevant to cobalamin deficiency, N2O effects, and their contribution to the clinical outcomes. [unreadable] [unreadable]